Magnitude of stromal hemangiogenesis correlates with histologic subtype of non-Hodgkin's lymphoma

Abstract

Purpose: Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1+ (VEGFR-1+) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68+ hemangiogenic cells and α-smooth muscle actin+ (α-SMA+) stromal cells correlates with neoangiogenesis and progression in human non-Hodgkin's lymphoma subtypes. Experimental Design: Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, α-SMA, and CD68 were examined by immunohistochemistry in 42 cases of non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia. Results: Compared with indolent lymphomas, there was a profound increase in recruitment of CD68+ cells and VEGFR-1+ neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68+ cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68+ cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in α-SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34+ microvessel density and lymphoma histologic subtype. Conclusions: Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1+CD68+VEGF-A+ cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas α-SMA+ stromal vascular network may be differentially targeted in CLL/SLL. © 2006 American Association for Cancer Research.